Erythropoietic Protoporphyria (EPP, MIM 177000) is a rare inherited disorder caused by the partial mitochondrial deficiency of ferrochelatase (FECH, EC 4.99.1.1.), the last enzyme in the heme biosynthesis pathway (Puy et al. 2010) (Balwani et al. 1993). FECH is an inner mitochondrial membrane enzyme that catalyzes the insertion of the ferrous iron into free protoporphyrin IX (PPIX) to form heme. FECH deficiency in bone marrow erythroid cells leads to the overproduction and accumulation of PPIX in the erythrocytes, and then to secondary accumulation of PPIX in the plasma, skin, bile and feces (Puy et al. 2010). The commonest clinical manifestation is lifelong acute photosensitivity of sun-exposed skin, first appearing in early childhood. Although it is generally a benign disease, hepatic complications such as cholelithiasis or, in about 2% of cases, cirrhosis with rapidly fatal liver disease, may occur (Bloomer et al. 1998; Meerman 2000; Lyoumi et al. 2011). Cases of EPP have been reported in Europe, USA, China and Japan. So far, no case of EPP has been reported in Black African subjects. Previously it was showed that the clinical outcome of EPP is due to the inheritance of a common hypomorphic allele in trans to a deleterious mutation; this reduces FECH activity below a critical 35% threshold of enzyme activity (Gouya et al. 1996; Gouya et al. 1999). A common intronic Single Nucleotide Polymorphism (SNP), IVS3-48C/T (rs2272783), is responsible for the low-expression of the hypomorphic IVS3-48C allele by modulating the use of a 3′ constitutive cryptic acceptor splice site located at the intron 3-exon 4 boundary, which leads to the pseudoexon inclusion of a portion of intron 3 (60% inclusion with the IVS3-48 C allele versus 20% with the T allele). The aberrantly-spliced mRNA includes a premature stop codon, and is degraded by a nonsense-mediated mRNA decay mechanism (NMD) (Gouya et al. 2002). In overt cases, this low, steady-state mRNA level of the hypomorphic allele also results in FECH enzyme deficiency. The overall FECH activity falls below a critical threshold of about 35% of normal, below which PPIX accumulation and photosensitivity occur (Gouya et al. 2006; Tahara et al. 2010). Several studies in USA, Europe, and Asia have confirmed that this mechanism is generally operative in EPP (Risheg et al. 2003; Wiman et al. 2003; Saruwatari et al. 2006; Kong et al. 2008; Whatley et al. 2010; Balwani et al. 2013). In France more than 90% of EPP patients show this striking inheritance pattern. Taken together, these findings suggest that therapeutic benefits in EPP patients might be achieved by even a modest increase in wild-type (WT) FECH protein. Thus, correcting this single splicing mutation represents an attractive strategy that could improve the condition of the vast majority of EPP patients. Antisense oligonucleotides (ASOs), which are generally used to inhibit gene expression, can also be used to modulate pre-mRNA splicing by targeting splice sites, or positive or negative elements that affect splice-site selection (Kole et al. 2012).